Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([O:8][CH:9]1[CH2:16][CH2:15][C:12]2([O:14][CH2:13]2)[CH:11]([C:17]2([CH3:25])[CH:19]([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[O:18]2)[CH:10]1[O:26][CH3:27])=[O:7].[N:28]1[CH:33]=CC=C[CH:29]=1.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=[O:36].CN>ClCCl.C(OCC)C.CO>[CH3:27][O:26][CH:10]1[CH:9]([O:8][C:6](=[O:7])[NH:5][CH2:4][CH2:3][CH2:2][O:1][C:35]([O:37][C:38]2[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=2)=[O:36])[CH2:16][CH2:15][C:12]2([O:14][CH2:13]2)[CH:11]1[C:17]1([CH3:25])[CH:19]([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[O:18]1.[CH3:27][O:26][CH:10]1[CH:9]([O:8][C:6](=[O:7])[NH:5][CH2:4][CH2:3][CH2:2][O:1][C:29](=[O:36])[NH:28][CH3:33])[CH2:16][CH2:15][C:12]2([O:14][CH2:13]2)[CH:11]1[C:17]1([CH3:25])[CH:19]([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[O:18]1
Reactant: COC1C(OC(=O)NCCCO)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Reactant: c1ccncc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: CNC(=O)OCCCNC(=O)OC1CCC2(CO2)C(C2(C)OC2CC=C(C)C)C1OC
Product: COC1C(OC(=O)NCCCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Reaction time: 2 h
Yield: 160.2 %

Procedure:
To a mixture of 6-(3-hydroxypropylcarbamoyloxy)-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (15 mg) and pyridine (12.3 mg) in dichloromethane (1 ml) was added portionwise 4-nitrophenyl chloroformate (32 mg) at ambient temperature. After stirring for 2 hours, 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-6-(4-nitrophenoxycarbonyloxypropylcarbamoyloxy)-1-oxaspiro[2,5]octane was prepared in the reaction mixture. To the mixture, 30% methanol solution of methylamine (7 mg) was added in one portion. The mixture was stirred for 1 hour at ambient temperature and diluted with diethyl ether (5 ml). The solution was washed with brine, 1N aqueous hydrochloric acid, 1N aqueous sodium hydroxide, and brine successively. The solvent was dried and evaporated in vacuo to give a crude oil, which was purified by column chromatography on silica gel eluted by diethyl ether to yield 5-methoxy-4-[2-methyl-3-[3-methyl-2-butenyl)oxiranyl]-6-[3-(methylcarbamoyloxy)propylcarbamoyloxy]-1-oxaspiro[2,5]octane (13.8 mg) as crystals.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:11][OH:12]>N1C=CC=CC=1>[C:1](=[N:11][OH:12])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 95 %

Procedure:
In a 50 ml round-bottom flask, a mixture of acetophenone, hydroxylamine hydrochloride in pyridine was stirred, at room temperature under nitrogen blanket, for five days. The reaction mixture was then concentrated under vacuum to remove most of pyridine. The oil was then distilled at 55° C. under 0.1 mbar. The product was obtained in 95% yield.
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14](=[O:22])[NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:23][C:2]1([F:1])[CH2:6][NH:5][C@H:4]([C:14]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:22])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)Nc1cnccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cnccn1)[C@@H]1CC(F)(F)CN1
Reaction time: 4 h

Procedure:
To a stirred solution of (S)-tert-butyl 4,4-difluoro-2-(pyrazin-2-ylcarbamoyl)pyrrolidine-1-carboxylate 116B (1.6 g, 4.87 mmol) in CH2Cl2(30 mL) was added trifluoroacetic acid (7.24 mL, 97 mmol). The mixture was stirred for 4 hrs, the solvent was evaporated to dryness and the residue 116C was used in the next reaction without further purification. LC/MS [M+H]+: 229; Ret time (Method F): 0.61 min.
Reaction SMILES: [O:1]1[C:13]2[C:4](=[CH:5][C:6]3[NH:10][C:9]([SH:11])=[N:8][C:7]=3[CH:12]=2)[O:3][CH2:2]1.Cl.Cl[CH2:16][C:17]1[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=1.[OH-].[Na+]>O>[CH3:25][O:24][C:21]1[C:20]([CH3:26])=[CH:19][N:18]=[C:17]([CH2:16][S:11][C:9]2[NH:10][C:6]3[CH:5]=[C:4]4[O:3][CH2:2][O:1][C:13]4=[CH:12][C:7]=3[N:8]=2)[C:22]=1[CH3:23]
Reactant: Sc1nc2cc3c(cc2[nH]1)OCO3
Reactant: COc1c(C)cnc(CCl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(C)cnc(CSc2nc3cc4c(cc3[nH]2)OCO4)c1C

Procedure:
14.8 g of 5H-1,3-dioxolo[4,5-f]benzimidazole-6-thiol were suspended in 300 ml of alcohol and the suspension was treated while cooling with ice with 17.0 g of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride. Thereafter, a solution of 6.0 g of sodium hydroxide in 150 ml of water was added dropwise thereto, the mixture was left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue was dissolved in 1000 ml of methylene chloride. The solution was washed firstly with 500 ml of 1.5N sodium hydroxide solution and then with 3×500 ml of water, dried over sodium sulfate and evaporated in vacuo. The product was purified on 300 g of silica gel using ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from methylene chloride/petroleum ether gave 6-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-5H-1,3-dioxolo[4,5-f]benzimidazole of melting point 178°-179°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([NH:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[C:24]([N+:32]([O-:34])=[O:33])[CH:23]=3)=[S:20])[CH3:16])[C:10]=2[OH:35])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].Cl.O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([NH:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[C:24]([N+:32]([O-:34])=[O:33])[CH:23]=3)=[S:20])[CH3:16])[C:10]=2[OH:35])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1ccc(NC(=S)NN=C(C)c2nn(C)c(-c3ccc(Cl)c(Cl)c3)c2O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)c([N+](=O)[O-])c1)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
Methyl 4-{[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)-carbonothioyl]amino}-2-nitrobenzoate (100 mg, 0.19 mmol) synthesized in Synthetic Example 104 was dissolved in methanol (3 ml), and 1 M sodium hydroxide aqueous solution (0.74 ml, 0.74 mmol) was added thereto, following by stirring overnight at room temperature. After completion of the stirring, 1 M hydrochloric acid (0.74 ml, 0.74 mmol) and water were added thereto. The precipitated solid was recovered by filtration, washed with water, isopropyl alcohol, and chloroform. The obtained solid was stirred in chloroform, and then filtered to obtain 37 mg of the desired product as a yellow solid (yield 48%).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12](F)[C:9]=1[C:10]#[N:11].[OH2:17].C[N:19](C=O)C>>[Br:7][C:8]1[C:9]2[C:10]([NH2:19])=[N:11][O:17][C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: N#Cc1c(F)cccc1Br
Reactant: CN(C)C=O
Reactant: O
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Nc1noc2cccc(Br)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of acetylhydroxamic acid (2.46 g, 32.8 mmol) and potassium tert-butoxide (3.68 g, 32.8 mmol) in DMF (40 mL) was stirred at room temperature for 30 minutes, treated with 2-bromo-6-fluorobenzonitrile (4.36 g, 21.8 mmol), stirred for three hours, poured into water, and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 5 to 20% ethyl acetate/hexanes to provide 2.5 g of the desired product. MS (ESI(+)) m/e 212.9, 214.9 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[N:3]1[CH2:8][CH2:7][C:6]([OH:11])([C:9]#N)[CH2:5][CH2:4]1.[OH-:13].[Na+].[C:15](=O)(O)[O-:16].[K+]>Cl.CO>[CH3:15][O:16][C:9]([C:6]1([OH:11])[CH2:7][CH2:8][N:3]([N:2]([CH3:12])[CH3:1])[CH2:4][CH2:5]1)=[O:13]
Reactant: O=C([O-])O
Reactant: [OH-]
Reactant: CN(C)N1CCC(O)(C#N)CC1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(O)CCN(N(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4.2 g 1-Dimethylamino-4-hydroxy-piperidine-4-carbonitrile is dissolved in 30 ml of a hydrochloric acid solution in methanol (10% HCl in methanol) and the reaction mixture is stirred at room temperature for 2 days. After 24 hours, the reaction vessel is saturated with hydrochloric acid gas. To bring the reaction to completion, the mixture is diluted with 100 ml methanol, saturated with hydrochloric acid gas and further stirred at room temperature overnight, then neutralized under cooling by addition of 40 ml NaOH 30% (to pH 6) and a saturated aqueous potassium bicarbonate solution (to pH 8). The solution is concentrated, the residue partitioned between ethyl acetate and water, the water layer extracted with ethyl acetate, the combined organic layer dried over sodium sulfate, and the solvent evaporated. The residue is purified by chromatography on silica gel, with ethyl acetate/methanol/triethylamine as a solvent (gradient 95/2.5/2.5 to 90/5/5). Thus, 2.27 g 1-Dimethylamino-4-hydroxy-piperidine-4-carboxylic acid methyl ester is obtained. 1H-NMR (CDCl3): 3.78 ppm (s, 3H), 2.90 ppm (s, broad, 1H), 2.82 ppm (m, 2H), 2.70 ppm (m, 2H), 2.41 ppm (s, 6H), 2.11 ppm (m, 2H), 1.69 ppm (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[CH:14][CH:13]=1.Cl>>[C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=1)[CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(Cl)cc3)CC2)c1
Agent: Cl
Product: CC(=O)c1cccc(OC(CCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(Cl)cc2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 1-(3-hydroxyphenyl)ethanone and N-(3-{1-[5-(4-chlorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.05 (s, br, 1H), 7.74-6.88 (m, 12H), 5.27-5.16 (m, 1H), 3.69-3.52 (m, br, 2H), 3.10-2.81 (br, 2H), 2.81-2.57 (m, br, 4H), 2.54 (s, 3H), 2.52-2.40 (m, br, 2H), 2.05-1.80 (m, br, 6H), 1.66-1.42 (m, br, 2H), 1.25 (d, 6H, J=6.8 Hz); Anal. Calc. for C34H42Cl2N2O3.0.5CH2Cl2.1.0H2O: C, 63.46; H, 6.91; N, 4.30. Found: C, 63.46; H, 7.09; N, 4.00. ESMS m/e: 561.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[CH:4][C:5](I)=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.C(N(CC)CC)C.[CH2:22]([S:24][CH2:25][C:26]([CH3:30])([OH:29])[C:27]#[CH:28])[CH3:23]>O1CCCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([CH:28]=[C:27]([C:26]([OH:29])([CH3:30])[CH2:25][S:24][CH2:22][CH3:23])[N:8]2[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[F:14]
Reactant: C#CC(C)(O)CSCC
Reactant: CS(=O)(=O)Nc1cc(Cl)c(F)cc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCSCC(C)(O)c1cc2cc(F)c(Cl)cc2n1S(C)(=O)=O

Procedure:
To a 50 mL round-bottom flask were added N-(5-chloro-4-fluoro-2-iodo-phenyl)-methanesulfonamide (0.30 g, 1.0 mmol), bis(triphenylphosphine) palladium(II) chloride (35 mg, 0.05 mmol) and copper (I) iodide (19 mg, 0.1 mmol). The flask was fitted with a septum and stirred under argon. Tetrahydrofuran (5 mL) and triethylamine (0.28 mL, 2.0 mmol) were then added via syringe. 1-Ethylsulfanyl-2-methyl-but-3-yn-2-ol (0.14 g, 1.0 mmol) in tetrahydrofuran (1 mL) was added via syringe and the reaction maintained with stirring at 50-60° C. for four hours. The solution was evaporated and the residue purified by column chromatography using dichloromethane as solvent to yield the title compound as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:27])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]([CH3:26])=[CH2:25])[C:5]2=[CH:4][CH:3]=1.[CH3:28][O:29][CH:30]([Si:32]([CH3:35])([CH3:34])[CH3:33])[CH3:31].[H-].[Li+].[Cl:38][CH2:39][CH2:40][CH2:41]I>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:27])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:41][CH2:40][CH2:39][Cl:38])[CH:11]3[C:24]([CH3:26])=[CH2:25])[C:5]2=[CH:4][CH:3]=1.[CH3:28][O:29][CH:30]([Si:32]([CH3:35])([CH3:34])[CH3:33])[CH3:31]
Reactant: ClCCCI
Reactant: C=C(C)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: COC(C)[Si](C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=C(C)C1N(CCCCl)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in example 24c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (1.57 g, 2.95 mmol) prepared in example 116a was reacted with LiH (2.3 g, 29.5 mmol) and 1-chloro-3-iodo-propane (6.04 g, 29.5 mmol) in N,N-dimethyl-formamide (100 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-1′-(3-chloro-propyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white form (Yield: 0.6 g, 33.5%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([C:11](=[N:21][OH:22])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)[C:5]=1F.[H-].[Na+]>CN(C=O)C.O.C(Cl)Cl>[CH3:1][O:2][C:3]([C:4]1[C:5]2[O:22][N:21]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=3)[C:6]=2[CH:7]=[CH:8][C:9]=1[Cl:10])=[O:24]
Reactant: CCc1ccc(NC(=NO)c2ccc(Cl)c(C(=O)OC)c2F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1ccc(Nc2noc3c(C(=O)OC)c(Cl)ccc23)cc1
Reaction time: 0.33 h

Procedure:
To a solution of methyl-6-chloro-3-(N-(4-ethylphenyl)-N′-hydroxycarbamimidoyl)-2-fluorobenzoate (225 mg, 641 μmol) in DMF (6.4 ml) chilled to 0° C. was added NaH (17 mg, 706 μmol) in one portion. The yellow solution evolved gas and immediately turned a dark orange color. After 20 min, the mixture was diluted with H2O and DCM, the layers were separated and the aqueous layer was extracted with DCM (2×). The organic layers were combined and washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound as a light brown solid, which was used for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH3:19])=[CH:7]2.C([Sn](CCCC)(CCCC)[C:25]([O:27]CC)=[CH2:26])CCC.Cl.CCN(CC)CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][C:8]1[C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[C:25](=[O:27])[CH3:26]
Reactant: Cc1cc2cccc(Br)c2nc1Nc1ccccc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc2cc(C)c(Nc3ccccc3)nc12
Temperature: 100 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
A solution of 8-bromo-3-methyl-N-phenylquinolin-2-amine (182.0 mg, 0.581 mmol), tributyl(1-ethoxyvinyl)stannane (Synthonix, Inc., Wake Forest, N.C.; 0.216 mL, 0.639 mmol), and Pd(PPh3)4 (33.6 mg, 0.029 mmol) in toluene (3.0 mL) was sparged with argon and stirred under argon at 100° C. for 16 h. The mixture was then concentrated in vacuo, and the residue was taken up in THF (3.0 mL). HCl (concentrated, aq.; 0.073 mL, 0.872 mmol) was added, and the resulting mixture was stirred at 60° C. for 15 min. Et3N (0.243 mL, 1.743 mmol) was added, and the mixture was concentrated onto silica gel. Chromatographic purification (silica gel, 0-50% EtOAc/hexanes) furnished 1-(3-methyl-2-(phenylamino)quinolin-8-yl)ethanone (161 mg, 0.583 mmol, 100% yield) as a yellow oil: 1H NMR (400 MHz, CD Cl3) δ ppm 7.79 (1H, s), 7.76 (1H, d, J=7.2 Hz), 7.64-7.72 (3H, m), 7.38 (2H, t, J=7.8 Hz), 7.29 (1H, t, J=7.5 Hz), 7.11 (1H, t, J=7.4 Hz), 6.52 (1H, br. s.), 2.76 (3H, s), 2.44 (3H, s). m/z (ESI, +ve) 277.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:26]=CN(C)C)=[N:5][C:6]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:7]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[N:10]=2)[N:8]=1)#[N:2].O.C([O-])(O)=O.[Na+].CCOC(C)=O>Cl.O1CCOCC1>[NH2:26][C:4]1[C:3]([C:1]#[N:2])=[N:8][C:7]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[N:10]=2)=[C:6]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[N:5]=1
Reactant: CC(C)n1nc(-c2nc(C#N)c(N=CN(C)C)nc2-c2ccc(F)cc2)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)n1nc(-c2nc(C#N)c(N)nc2-c2ccc(F)cc2)ccc1=O
Yield: 69432.6 %

Procedure:
A solution of N′-[3-cyano-6-(4-fluorophenyl)-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinyl]-N,N-dimethylimidoformamide (100 mg) in 4N HCl in dioxane (2 ml) and water (2 ml) was stirred at 25° C. for 15 hours. Water, aq. NaHCO3 and EtOAc were added to the reaction mixture. The organic layer was separated, and dried over MgSO4. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain 3-amino-5-(4-fluorophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarbonitrile (60 g) as white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][OH:18])[CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.Cl[C:20]1[CH:36]=[C:24]2[N:25](C(OC(C)(C)C)=O)[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:37])[N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[CH2:17][O:18][C:20]1[CH:36]=[C:24]2[NH:25][CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:37])[N:21]=1
Reactant: CC(C)(C)OC(=O)N1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(Oc2cccc(F)c2)c(F)c1
Product: O=c1nc(OCc2cc(F)c(Oc3cccc(F)c3)c(F)c2)cc2n1CCCN2

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E111 starting from (3,5-difluoro-4-(3-fluorophenoxyl)phenyl)methanol and tert-butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH:22]=[CH:23]N(C)C)=[CH:17][C:16]=1[N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30].C(OCC)(=O)C>C(O)(=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:23][CH:22]=2)=[CH:17][C:16]=1[N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30]
Reactant: CN(C)C=CC(=O)c1ccc(Cl)c(N(C)S(C)(=O)=O)c1
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN(c1cc(-c2ccnc3c(C(=O)c4cccs4)cnn23)ccc1Cl)S(C)(=O)=O
Yield: 73 %

Procedure:
A mixture of 0.076 g (0.39 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.124 g (0.39 mmol) of (N-[2-chloro-5-(3-dimethylamino-acryloyl)-phenyl]-N-methyl-methanesulfonamide in 10 ml of glacial acetic acid was refluxed for 1.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 128 mg of N-{2-chloro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a solid (yield 73%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](O)=O)=[CH:5][CH:4]=1.[N:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]([NH:27][NH2:28])=O)=[CH:24][C:19]=2[NH:18][CH:17]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1.O=P(Cl)(Cl)Cl>>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[S:38][C:25]([C:23]3[CH:22]=[CH:21][C:20]4[NH:16][CH:17]=[N:18][C:19]=4[CH:24]=3)=[N:27][N:28]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)s2)cc1

Procedure:
The compound was synthesized starting from 3-(4-trifluoromethylphenyl)propionic acid (219 mg; 1 mmol), benzimidazol-5-carbohydrazide (176 mg; 1 mmol), Lawesson's reagent (606 mg; 1.5 mmol) and POCl3 (0.137 ml; 1.5 mmol) as described in method 3; yield: 0.017 g (4.5%); MS m/z: 375.1 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.22 (t, 2H, 3J=7.5 Hz); 3.52 (t, 2H, 3J=7.5 Hz); 7.53-7.55 (m, 2H); 7.65-7.67 (m, 2H); 7.84 (d, 1H, 3J=8.7 Hz); 7.92 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 8.22-8.23 (m, 1H); 8.93 (s, 1H); HPLC (METHOD [A]): rt 14.82 min (98.3%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([CH3:9])=[C:6]([F:8])[CH:7]=1.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:6]1[CH:7]=[C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([F:13])[CH:19]=2)[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]=1[CH3:9]
Reactant: Cc1c(F)cc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1c(F)cc(-c2cccc(F)c2)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 75.3 %

Procedure:
A mixture of 5-bromo-1-fluoro-2-methyl-3-nitro-benzene (5.0 g, 21.31 mmol, 1.0 eq), 3-fluorophenylboronic acid (3.29 g, 23.8 mmol, 1.1 eq), Pd(PPh3)4 (1.2 g, 1.07 mmol, 0.05 eq) and K2CO3 (11.8 g, 85.5 mmol, 4 eq) in a mixture of dioxane (150 mL) and EtOH (50 mL) was heated at 80° C. under N2 overnight. After cooling to room temperature the reaction was poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as an oil (4.0 g, 75%). This material was used without further purification.